On June 11, 2021 AbbVie (NYSE: ABBV) reported results from a four-year follow-up analysis of the Phase 3 CLL14 trial, which showed that previously untreated patients with chronic lymphocytic leukemia (CLL) with coexisting conditions who were treated with VENCLYXTO/VENCLEXTA (venetoclax) plus obinutuzumab continued to show longer progression-free survival (PFS) and higher rates of undetectable minimal residual disease (MRD) compared to patients receiving a standard of care chemoimmunotherapy regimen of obinutuzumab and chlorambucil (Press release, AbbVie, JUN 11, 2021, View Source [SID1234583863]). The data were presented for the first time today during the virtual 26th European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress (abstract #S146).

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"The CLL14 trial results observed after four years of follow-up with treatment of venetoclax plus obinutuzumab show that these patients can experience long-lasting responses without disease progression, years after stopping treatment," said Mohamed Zaki, M.D., Ph.D., vice president and head, global oncology development, AbbVie.

After a median follow-up of more than four years (52.4 months), patients treated with the VENCLYXTO/VENCLEXTA and obinutuzumab combination (n=216) continued to demonstrate longer PFS compared to patients on treatment with obinutuzumab and chlorambucil, the risk of disease progression or death was reduced by 67 percent (n=216; median not reached compared to 36.4 months; hazard ratio [HR] 0.33 [95% CI 0.25-0.45]); results are descriptive. At four years after randomization, the PFS rate for patients treated with the VENCLYXTO/VENCLEXTA-based combination was 74 percent compared to 35.4 percent for patients treated with obinutuzumab and chlorambucil. The improvement in PFS was observed across all clinical and biological risk groups, including patients with TP53 mutation, 17p deletion and unmutated IGHV status.1

Additionally, assessment of MRD in peripheral blood 30 months after the end of treatment showed that 26.9 percent of patients treated with the VENCLYXTO/VENCLEXTA-based combination still had undetectable MRD (<10-4) compared to 3.2 percent of patients in the obinutuzumab plus chlorambucil arm.1 Undetectable MRD occurs when less than one CLL cell per 10,000 lymphocytes can be detected in the blood or bone marrow using sensitive analytical methods.2

No new safety signals were observed in the four-year follow-up analysis.1 The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with obinutuzumab were pneumonia, sepsis, febrile neutropenia, and TLS.3

"CLL is considered an incurable disease and becomes more difficult to treat each time a patient experiences a relapse, so a key treatment goal is to maintain remission for as long as possible. The four- year results of the CLL14 study show that 74 percent of patients treated with fixed-duration venetoclax-obinutuzumab remain without PFS event, more than three years after treatment cessation," said Othman Al-Sawaf, M.D., lead investigator of the CLL14 study, hematologist-oncologist at the University Hospital Cologne in Germany, and study physician at the German CLL Study Group. "This highlights how durable the remissions are after 12 treatment cycles in the vast majority of patients, suggesting the venetoclax-obinutuzumab combination regimen as an effective option for patients with previously untreated CLL."

CLL is a slow-growing form of leukemia, or blood cancer, in which too many immature lymphocytes (a type of white blood cell) are found predominantly in the blood and bone marrow. CLL is the most common form of leukemia in the Western Hemisphere, accounting for approximately one third of new leukemia diagnoses and nearly 95,000 new cases in Europe each year.4,5,6

VENCLYXTO/VENCLEXTA is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

About the CLL14 Phase 3 Trial3,7,8
The prospective, multicenter, open-label, randomized Phase 3 CLL14 trial, which was conducted in close collaboration with the German CLL Study Group (DCLLSG), evaluated the efficacy and safety of a combined regimen of VENCLYXTO/VENCLEXTA and obinutuzumab (n=216) versus obinutuzumab and chlorambucil (n=216) in previously untreated patients with CLL and coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance <70 mL/min). The therapies were administered for a fixed duration of 12 months for VENCLYXTO/VENCLEXTA in combination with six cycles of obinutuzumab. The trial enrolled 432 patients, all of whom were previously untreated according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Efficacy was based on PFS as assessed by an independent review committee.

Key secondary endpoints were rates of MRD in peripheral blood and bone marrow, overall and complete response rates, MRD in complete response in peripheral blood and bone marrow, and overall survival.

The four-year, follow-up analysis showed an OS rate of 85.4% with Ven-Obi versus 83.1% with chlorambucil in combination with obinutuzumab (Obi-Clb; HR 0.85, 95% CI [0.54-1.35]; P=0.49).

In patients with CLL receiving combination therapy with obinutuzumab, serious adverse reactions (ARs) were most often due to febrile neutropenia and pneumonia (5 percent each). The most common ARs (≥20 percent) of any grade were neutropenia (60 percent), diarrhea (28 percent), and fatigue (21 percent). Fatal ARs that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2 percent (4/212) of patients, most often from infection.

About VENCLYXTO (venetoclax)

VENCLYXTO (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.

VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers. Venetoclax is approved in more than 80 countries, including the U.S.

Indication and Important VENCLYXTO (venetoclax) EU Safety Information3

Indications

Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).

Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.

Venclyxto monotherapy is indicated for the treatment of CLL:

In the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
In the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.
Venclyxto in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.

Contraindications

Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumour lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as Venclyxto efficacy may be reduced.

Special Warnings & Precautions for Use

Tumour Lysis syndrome, including fatal events, has occurred in patients when treated with Venclyxto. For CLL and AML, please refer to the indication-specific recommendations for prevention of TLS in the Venclyxto summary of product characteristic (SmPC).

Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS. The risk of TLS is a continuum based on multiple factors, including comorbidities. Venclyxto poses a risk for TLS at initiation and during the dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venclyxto and at each dose increase.

Neutropenia (grade 3 or 4) has been reported. Complete blood counts should be monitored throughout the treatment period.

In patients with AML, neutropenia (grade 3 or 4) is common before starting treatment. The neutrophil counts can worsen with Venetoclax in combination with a hypomethylating agent. Neutropenia can recur with subsequent cycles of therapy. Dose modification and interruptions for cytopenias are dependent on remission status.

For CLL and AML, please refer to the indication-specific recommendations for dose modifications for toxicities in the Venclyxto SmPC.

Serious infections including sepsis with fatal outcome have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections should receive prompt treatment including antimicrobials and dose interruption or reduction as appropriate.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions

In CLL and AML CYP3A inhibitors may increase Venclyxto plasma concentrations.

In CLL, at initiation and dose-titration phase, Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, please refer to the recommendations for dose modifications in the Venclyxto SmPC.

In AML, please refer to the AML-specific recommendation for dose modifications for potential interactions with CYP3A inhibitors, in the VENCLYXTO SmPC.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease Venclyxto plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions

CLL

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination studies with obinutuzumab or rituximab were neutropenia, diarrhoea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with obinutuzumab or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS. In the monotherapy studies, the most frequently reported serious adverse reactions (>=2%) were pneumonia and febrile neutropenia.

Discontinuations due to adverse reactions occurred in 16% of patients treated with venetoclax in combination with obinutuzumab or rituximab in the CLL14 and Murano studies, respectively. In the monotherapy studies with venetoclax, 11% of patients discontinued due to adverse reactions.

Dosage reductions due to adverse reactions occurred in 21% of patients treated with the combination of venetoclax and obinutuzumab in CLL14, in 15% of patients treated with the combination of venetoclax and rituximab in Murano, and in 14% of patients treated with venetoclax in the monotherapy studies. The most common adverse reaction that led to dose interruptions was neutropenia.

AML

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in combination with azacitidine or decitabine in the VIALE-A and M14-358, respectively, were thrombocytopenia, neutropenia, febrile neutropenia, nausea, diarrhoea, vomiting, anaemia, fatigue, pneumonia, hypokalaemia, and decreased appetite, haemorrhage, dizziness/syncope, hypotension, headache, abdominal pain, and anaemia.

The most frequently reported serious adverse reactions (≥5%) in patients receiving venetoclax in combination with azacitidine were febrile neutropenia, pneumonia, sepsis and haemorrhage. In M14-358, the most frequently reported serious adverse reactions (≥5%) were febrile neutropenia, pneumonia, bacteraemia and sepsis.

Discontinuations due to adverse reactions occurred in 24% of patients treated with venetoclax in combination with azacitidine in the VIALE-A study, and 26% of patients treated with venetoclax in combination with decitabine in the M14-358 study, respectively.

Dosage reductions due to adverse reactions occurred in 2% of patients in VIALE-A, and in 6% of patients in M14-358. Venetoclax dose interruptions due to adverse reactions occurred in 72% and 65% of patients, respectively. The most common adverse reaction that led to dose interruption (>10%) of Venetoclax in VIALE-A, were febrile neutropenia, neutropenia, pneumonia, and thrombocytopenia. The most common adverse reactions that led to dose interruption (≥5%) of venetoclax in M14-358 were febrile neutropenia, neutropenia/neutrophil count decreased, pneumonia, platelet count decreased, and white blood cell count decreased.

Special Populations

Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation and during the dose-titration phase. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined.

For patients with severe (Child-Pugh C) hepatic impairment, a dose reduction of at least 50% throughout treatment is recommended.

Venclyxto may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See Venclyxto (venetoclax) SmPC at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie in Oncology
At AbbVie, we are committed to transforming standards of care for multiple blood cancers while advancing a dynamic pipeline of investigational therapies across a range of cancer types. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potentially breakthrough medicines. We are evaluating more than 20 investigational medicines in over 300 clinical trials across some of the world’s most widespread and debilitating cancers. As we work to have a remarkable impact on people’s lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit View Source

On June 11, 2021 Vertex Pharmaceuticals Incorporated (Nasdaq:VRTX) and CRISPR Therapeutics (Nasdaq:CRSP) reported new data on 22 patients, with follow-up of at least 3 months, and ranging from 4 months to 26 months, treated with the investigational CRISPR/Cas9-based gene-editing therapy, CTX001, that show a consistent and sustained response to treatment (Press release, Vertex Pharmaceuticals, JUN 11, 2021, View Source [SID1234583849]). CTX001 is being investigated in two ongoing Phase 1/2 clinical trials as a potential one-time therapy for patients suffering from transfusion-dependent beta thalassemia (TDT) and severe sickle cell disease (SCD). In total, more than 40 patients have been dosed across both studies to date.

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All 15 patients with TDT, including six who have the beta zero/beta zero or other severe genotypes, were transfusion-free at last follow-up, and all seven patients with severe SCD were free of vaso-occlusive crises (VOCs) from CTX001 infusion through last follow-up. Five patients with TDT and two patients with SCD now have follow-up of greater than one year, demonstrating a stable and durable response to treatment. These data are available as e-posters beginning on June 11, 2021, at 09:00 CEST, and a partial presentation of these data were presented during the Joint EHA (Free EHA Whitepaper)-ASH Symposium on June 10, 2021 from 17:30-18:30 CEST. A summary of the results from the CLIMB-111 and CLIMB-121 Phase 1/2 clinical trials is provided below.

"The data presented today in 22 patients are impressive in both the consistency and durability of effect. These results add to the growing body of evidence that CTX001 may hold the promise for a one-time functional cure for sickle cell disease and beta thalassemia. We are working with urgency to complete enrollment and look forward to finalizing regulatory discussions and moving towards filing," said Reshma Kewalramani, M.D., Chief Executive Officer and President at Vertex.

"The continued progress and momentum of CTX001 validate the role that CRISPR gene-editing technology could have in the future of therapeutics," added Samarth Kulkarni, Ph.D., Chief Executive Officer at CRISPR Therapeutics. "We are excited about these results and look forward to additional longer-term data and to moving this investigational medicine forward for a larger population of patients with these two devastating diseases."

"As a physician caring for patients suffering from beta thalassemia, I have a high sense of urgency for novel and efficacious treatments," said Dr. Franco Locatelli, Professor of Pediatrics at the Sapienza University of Rome, Director of the Department of Pediatric Hematology and Oncology at Bambino Gesù Children’s Hospital. "These results suggest the potential for a durable benefit for patients with transfusion-dependent beta thalassemia."

"It is thrilling to work on a groundbreaking program like CTX001," said Dr. Stephan Grupp, Section Chief, Cellular Therapy and Transplant, Division of Oncology, Children’s Hospital of Philadelphia. "This approach uses CRISPR/Cas9 gene editing to enable the patient’s own cells to produce fetal hemoglobin, and to see results that demonstrate the potential for a treatment that may transform the lives of many patients is an exciting time for me and the team."

CLIMB-111 Trial in TDT: Updated Results
The 15 patients with TDT reported at EHA (Free EHA Whitepaper) are patients who had reached at least three months of follow-up after CTX001 dosing and therefore could be assessed for initial safety and efficacy. All 15 patients showed a similar pattern of response, with rapid and sustained increases in total hemoglobin, fetal hemoglobin and transfusion independence.

All 15 patients were transfusion independent with follow-up ranging from 4 to 26 months after CTX001 infusion and had clinically meaningful improvements in total hemoglobin from 8.9 to 16.9 g/dL and fetal hemoglobin from 67.3% to 99.6% at last visit.

Bone marrow allelic editing data collected from 10 patients with at least 6 months of follow-up, of which five patients had at least 12 months of follow-up and one patient had at least 24 months of follow-up, demonstrated a durable effect.

The safety data from all 15 patients were generally consistent with an autologous stem cell transplant and myeloablative conditioning. As previously reported, there were four serious adverse events (SAEs) considered related or possibly related to CTX001 reported in one patient: headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and idiopathic pneumonia syndrome. All four SAEs occurred in the context of HLH and have resolved. The majority of non-serious adverse events were considered mild to moderate.

The presentations at EHA (Free EHA Whitepaper) and the data summarized in this press release cover all TDT patients dosed with CTX001 with three or more months of follow-up as of the data cut on March 30, 2021. In addition to the data presented above, a TDT patient, with less than three months of follow-up and therefore not included in the data cut, experienced an SAE; this SAE of cerebellar hemorrhage, which was considered related to busulfan conditioning, has resolved.

Enrollment and dosing are ongoing.

CLIMB-121 Trial in Severe SCD: Updated Results
The seven patients reported at EHA (Free EHA Whitepaper) are patients who had reached at least three months of follow-up after CTX001 dosing and therefore could be assessed for initial safety and efficacy. All seven patients showed a similar pattern of response, with rapid and sustained increases in total hemoglobin and fetal hemoglobin, as well as elimination of VOCs.

All seven patients remained VOC-free with follow-up ranging from five to 22 months after CTX001 infusion and had clinically meaningful improvements in total hemoglobin from 11 to 15.9 g/dL and fetal hemoglobin levels from 39.6% to 49.6% at last visit.

Bone marrow allelic editing data collected from four patients who have at least six months of follow-up, of which two had 12 months of follow-up, demonstrated a durable effect.

The safety data from all seven patients were generally consistent with an autologous stem cell transplant and myeloablative conditioning. There were no SAEs considered related to CTX001, and the majority of non-serious adverse events were considered mild to moderate.

Enrollment and dosing are ongoing.

About CTX001
CTX001 is an investigational, autologous, ex vivo CRISPR/Cas9 gene-edited therapy that is being evaluated for patients suffering from TDT or severe SCD, in which a patient’s hematopoietic stem cells are edited to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is a form of the oxygen-carrying hemoglobin that is naturally present at birth, which then switches to the adult form of hemoglobin. The elevation of HbF by CTX001 has the potential to alleviate or eliminate transfusion requirements for patients with TDT and reduce or eliminate painful and debilitating sickle crises for patients with SCD. Earlier results from these ongoing trials were published as a Brief Report in The New England Journal of Medicine in January of 2021.

Based on progress in this program to date, CTX001 has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the U.S. Food and Drug Administration (FDA) for both TDT and SCD. CTX001 has also been granted Orphan Drug Designation from the European Commission, as well as Priority Medicines (PRIME) designation from the European Medicines Agency (EMA), for both TDT and SCD.

Among gene-editing approaches being investigated/evaluated for TDT and SCD, CTX001 is the furthest advanced in clinical development.

About CLIMB-111
The ongoing Phase 1/2 open-label trial, CLIMB-Thal-111, is designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 12 to 35 with TDT. The trial will enroll up to 45 patients and follow patients for approximately two years after infusion. Each patient will be asked to participate in a long-term follow-up trial.

About CLIMB-121
The ongoing Phase 1/2 open-label trial, CLIMB-SCD-121, is designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 12 to 35 with severe SCD. The trial will enroll up to 45 patients and follow patients for approximately two years after infusion. Each patient will be asked to participate in a long-term follow-up trial.

About CLIMB-131
This is a long-term, open-label trial to evaluate the safety and efficacy of CTX001 in patients who received CTX001 in CLIMB-111 or CLIMB-121. The trial is designed to follow participants for up to 15 years after CTX001 infusion.

About the Gene-Editing Process in These Trials
Patients who enroll in these trials will have their own hematopoietic stem and progenitor cells collected from peripheral blood. The patient’s cells will be edited using the CRISPR/Cas9 technology. The edited cells, CTX001, will then be infused back into the patient as part of a stem cell transplant, a process which involves, among other things, a patient being treated with myeloablative busulfan conditioning. Patients undergoing stem cell transplants may also encounter side effects (ranging from mild to severe) that are unrelated to the administration of CTX001. Patients will initially be monitored to determine when the edited cells begin to produce mature blood cells, a process known as engraftment. After engraftment, patients will continue to be monitored to track the impact of CTX001 on multiple measures of disease and for safety.

About the Vertex-CRISPR Collaboration
Vertex and CRISPR Therapeutics entered into a strategic research collaboration in 2015 focused on the use of CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. CTX001 represents the first potential treatment to emerge from the joint research program. Under a recently amended collaboration agreement, Vertex will lead global development, manufacturing and commercialization of CTX001 and split program costs and profits worldwide 60/40 with CRISPR Therapeutics.

On June 11, 2021 Caelum Biosciences and Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) reported new Phase 2 safety and tolerability data for CAEL-101, a potentially first-in-class amyloid fibril targeted therapy, in combination with standard-of-care (SoC) therapy in patients with AL amyloidosis (Press release, Caelum Biosciences, JUN 11, 2021, View Source [SID1234583848]). The data, presented in two e-posters at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress 2021, strengthen the safety and tolerability profile of CAEL-101, further support the dose selection for the ongoing Phase 3 study, and suggest possible cardiac and renal response. An e-poster featuring the first data from a new arm of the study demonstrated that CAEL-101 administered in combination with cyclophosphamide-bortezomib-dexamethasone (CyBorD) plus daratumumab was generally safe and well-tolerated in the first four weeks of treatment. Data presented in a second e-poster showed longer-term evidence that CAEL-101 in combination with CyBorD was generally well-tolerated for a median treatment duration of 49 weeks, and exploratory clinical biomarker data suggesting possible cardiac disease improvements and renal response among patients with cardiac or renal impairment at baseline, respectively.

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"AL amyloidosis is a relentless disease that is particularly devastating when it impacts the heart, with some of these patients facing a median survival of less than one year following diagnosis. Current treatments for AL amyloidosis are designed to prevent or suppress the formation of new amyloids, but they do not address the existing amyloid buildup in the involved organs like the heart and kidneys, which can result in continued organ damage and can ultimately be fatal," said Michael Spector, President and Chief Executive Officer of Caelum. "Understanding that CAEL-101 has the potential to be the first therapy to address the devastating organ damage caused by AL amyloidosis, we are urgently working to advance the ongoing CARES Phase 3 program in collaboration with Alexion."

Safety and Tolerability of CAEL-101 in Combination with Cyclophosphamide-Bortezomib-Dexamethasone and Daratumumab in Patients with AL amyloidosis (#EP1017)

As was previously announced, the Phase 2 study of CAEL‑101 in combination with CyBorD met its primary objectives, supporting the safety and tolerability of CAEL-101 and the selection of the 1000 mg/m2 dose for the ongoing Phase 3 study. Results presented from an additional study arm that included 11 patients receiving CAEL-101 (1000 mg/m2 dose) in combination with CyBorD plus daratumumab suggested that treatment with this combination was generally well-tolerated in the first four weeks of treatment. Specifically, adding daratumumab to the CAEL-101 and CyBorD regimen did not result in any new safety signals, nor did it alter the pharmacokinetic (PK) exposure to CAEL-101. The most common adverse events (AEs) reported in the first four weeks in the additional arm were nausea, constipation, and insomnia.

Safety and Tolerability of CAEL-101 in Patients with AL Amyloidosis in a Phase 2 Study for a Median of 49 Weeks (#EP1018)

Additional longer-term data presented from the Phase 2 study demonstrated that CAEL-101 in combination with CyBorD in patients with AL amyloidosis (N=13) was generally well tolerated up to a median treatment duration of 49 weeks (range 12-57 weeks), with most patients having received more than 20 infusions of CAEL-101. The most common AEs reported were diarrhea, nausea, fatigue, rash, and anemia. In addition, exploratory clinical biomarker evaluations showed early signals suggesting possible cardiac and renal response. Specifically, median percent changes for biomarkers of cardiac disease (cTnT and NT-proBNP) were lower at each subsequent time point measured, suggesting improvement in cardiac function among eight patients with active cardiac disease at baseline. Additionally, seven patients with active renal impairment at baseline demonstrated renal response, as defined by a decrease of at least 30 percent in proteinuria (an excess of protein in the urine) following treatment.

"We are grateful to clinical trial participants who are essential to advancing our work towards new treatment options for AL amyloidosis," said John Orloff, M.D., Executive Vice President and Head of Research and Development at Alexion. "We remain committed to working together with the AL amyloidosis community and Caelum to evaluate the potential of CAEL-101 as a potentially first-in-class treatment option for patients who are living with this devastating disease."

As was previously announced, the Cardiac Amyloid Reaching for Extended Survival (CARES) Phase 3 clinical program to evaluate CAEL-101 in combination with SoC therapy in AL amyloidosis has begun. Enrollment is underway in two parallel Phase 3 studies – one in patients with Mayo stage IIIa disease (ClinicalTrials.gov Identifier: NCT04512235) and one in patients with Mayo stage IIIb disease (ClinicalTrials.gov Identifier: NCT04504825) – and will collectively enroll approximately 370 patients globally.

About the CAEL-101 Phase 2 Study

The Phase 2 multicenter, open-label, dose-selection study (ClinicalTrials.gov Identifier: NCT04304144) is designed to evaluate the safety and tolerability of CAEL-101 in combination with standard of care (SoC) therapy for patients with AL amyloidosis and determine the recommended dose for Phase 3 studies. The study is divided into two parts: Part A examined CAEL-101 in combination with cyclophosphamide-bortezomib-dexamethasone (CyBorD) and employed a 3+3 dose escalation design (cohort 1 – 500 mg/m2; cohort 2 – 750 mg/m2 ; cohort 3 1000 mg/m2); Part A patients were subsequently up titrated to 1000mg/m2, once this was identified as the Phase 3 dose. Part B is examining CAEL-101 at the 1000 mg/m2 dose in combination with CyBorD plus daratumumab. Patients from Parts A and B receive CAEL-101 therapy weekly for the four-week observation period followed by CAEL-101 doses every other week thereafter, all while continuing to receive SoC therapy. Patients continue to receive CAEL-101 per protocol until the end of the study or discontinuation.

About CAEL-101

CAEL-101 is a first-in-class monoclonal antibody (mAb) designed to improve organ function by reducing or eliminating amyloid deposits in the tissues and organs of patients with AL amyloidosis. The antibody is designed to bind to misfolded light chain proteins and amyloid and shows binding to both kappa and lambda subtypes. In a Phase 1a/1b study, CAEL-101 demonstrated improved organ function, including cardiac and renal function, in 27 patients with relapsed and refractory AL amyloidosis who had previously not had an organ response to standard of care therapy. CAEL-101 has received Orphan Drug Designation from both the U.S. Food and Drug Administration and European Medicine Agency as a potential therapy for patients with AL amyloidosis.

About AL Amyloidosis

AL amyloidosis is a rare systemic disorder caused by an abnormality of plasma cells in the bone marrow. Misfolded immunoglobulin light chains produced by plasma cells aggregate and form fibrils that deposit in tissues and organs. This deposition can cause widespread and progressive organ damage and high mortality rates, with death most frequently occurring as a result of cardiac failure. Current standard of care includes plasma cell directed chemotherapy and autologous stem cell transplant, but these therapies do not address the organ dysfunction caused by amyloid deposition, and up to 80 percent of patients are ineligible for transplant.

AL amyloidosis is a rare disease but is the most common form of systemic amyloidosis. There are approximately 22,000 patients across the United States, France, Germany, Italy, Spain and the United Kingdom. AL amyloidosis has a one-year mortality rate of 47 percent, 76 percent of which is caused by cardiac amyloidosis.

On June 11, 2021 Bristol Myers Squibb (NYSE: BMY) and Acceleron Pharma Inc. (NASDAQ: XLRN) reported the first data from the Phase 2 BEYOND study evaluating Reblozyl (luspatercept-aamt), a first-in-class erythroid maturation agent, plus best supportive care in adult patients with non-transfusion dependent (NTD) beta thalassemia, were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Congress as part of its Presidential Symposium (Abstract #S101) (Press release, Bristol-Myers Squibb, JUN 11, 2021, View Source [SID1234583847]). Results demonstrated that 77.7% of patients treated with Reblozyl achieved a hemoglobin increase (≥1.0 gram/deciliter) compared to 0% of patients in the placebo arm. Changes in patient-reported outcomes also correlated with increases in hemoglobin. NTD beta thalassemia is a term used to describe patients who do not require lifelong regular red blood cell (RBC) transfusions for survival, although they may require occasional or even frequent transfusions, usually for defined periods of time.

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"Patients with non-transfusion dependent beta thalassemia experience chronic anemia and iron overload, which may lead to a range of clinical complications, and treatment options are greatly needed," said Ali Taher, M.D., Ph.D., FRCP, of American University of Beirut and BEYOND study investigator. "Results from the BEYOND study show the clinical potential of luspatercept to sustain the elevation of hemoglobin levels in a majority of patients regardless of their baseline hemoglobin status, and improvements were noted in quality of life outcomes in adults with non-transfusion dependent beta thalassemia."

Reblozyl is the first and only erythroid maturation agent approved in the European Union, United States and Canada to address anemia-associated beta thalassemia and lower-risk myelodysplastic syndromes, representing an important class of therapy for eligible patients.1,2,3

"We are very encouraged by the magnitude of improvement seen among Reblozyl-treated patients in the BEYOND trial," said Habib Dable, President and Chief Executive Officer of Acceleron. "These data further strengthen our confidence in Reblozyl’s potential to become a meaningful option for this important, underserved patient population around the world."

"The results we are presenting at EHA (Free EHA Whitepaper) continue to highlight multiple benefits observed with Reblozyl to treat anemia and achieve transfusion independence, as well as show its potential for patients with non-transfusion dependent disease who face a range of serious, often lifelong health complications," said Noah Berkowitz, M.D., Ph.D., senior vice president, Hematology Development, Bristol Myers Squibb. "Along with our partners at Acceleron, we are committed to advancing our clinical program for Reblozyl for patients living with anemia-associated blood disorders."

BEYOND Study Results

BEYOND is a Phase 2, randomized, double-blind, placebo-controlled multi-center study to determine the efficacy and safety of Reblozyl versus placebo in adults with non-transfusion dependent (NTD) beta thalassemia. Eligible patients were ≥18 years with beta thalassemia or hemoglobin (Hb) E beta thalassemia and received ≤5 red blood cell (RBC) units in the 24 weeks prior to randomization, with mean baseline Hb ≤10.0 gram/deciliter (g/dL).4

In the study, 145 patients were randomized 2:1 to receive Reblozyl, 1 milligram/kilogram (titration up to 1.25 mg/kg) or placebo subcutaneously every 3 weeks for ≥48 weeks. Patients in both arms continued to receive best supportive care, including RBC transfusions as indicated and iron chelation therapy. The primary endpoint was achievement of ≥1.0 g/dL mean Hb increase from baseline over a continuous 12-week interval from weeks 13-24 in the absence of RBC transfusions. Secondary endpoints included proportion of patients who remained transfusion free over weeks 1-24, who achieved mean Hb increase of ≥1.5 g/dL from baseline to weeks 13-24, and mean change in NTD beta thalassemia patient-reported outcome tiredness and weakness (NTDT-PRO T/W) domain scores (higher scores reflect worse quality of life; QoL).4

Over a continuous 12-week interval from weeks 13-24 in the absence of RBC transfusions, 74 of 96 (77.1%) patients in the Reblozyl treatment arm achieved the study’s primary endpoint, ≥1.0 g/dL mean Hb increase from baseline, versus 0 of 49 (0%) patients in the placebo arm (P<0.0001). The primary endpoint was achieved by 40 of 55 (72.7%) patients in the Reblozyl arm with mean baseline Hb of <8.5 g/dL versus 0 (0%) of patients in the placebo arm (P<0.0001), and 34 of 41 patients (82.9%) with mean baseline Hb of ≥8.5 g/dL versus 0 patients (0%) in the placebo arm (P<0.0001). In a key secondary endpoint of the study, during weeks 13-24, 50 of 96 patients (52.1%) in the Reblozyl arm achieved mean Hb increase of ≥1.5 g/dL compared to baseline versus 0 patients (0%) in the placebo arm (P<0.0001). 89.6% of patients in the Reblozyl arm remained transfusion free at weeks 1-24 versus 67.3% of patients in the placebo arm (P=0.0013). Improvements in patient-reported QoL outcomes (tiredness and weakness) were also observed to correlate with Hb increases.

The most common treatment-emergent adverse events of any grade occurring in ≥5% of patients were bone pain (36.5% Reblozyl versus 6.1% placebo), headache (30.2% versus 20.4%), and arthralgia (29.2% versus 14.3%). No malignancies or thromboembolic events were reported in patients treated with Reblozyl.

About Beta Thalassemia

Beta thalassemia is an inherited blood disorder caused by a genetic defect in hemoglobin. It is one of the most common autosomal recessive disorders, and the total annual incidence of symptomatic individuals is estimated at 1 in 100,000 people globally and 1 in 10,000 people in the European Union.5 The disease is associated with ineffective erythropoiesis, which results in the production of fewer and less healthy red blood cells (RBCs), often leading to severe anemia—a condition that can be debilitating and can lead to other complications for patients—as well as other serious health issues. Treatment options for anemia associated with beta thalassemia are limited, consisting mainly of frequent RBC transfusions that have the potential to contribute to iron overload, which can cause serious complications such as organ damage.5 Non-transfusion dependent thalassemia is a term used to describe patients who do not require lifelong regular transfusions for survival, although they may experience a range of clinical complications and require occasional or even frequent transfusions, usually for defined periods of time.6

About Reblozyl

Reblozyl (luspatercept-aamt), a first-in-class erythroid maturation agent, promotes late-stage red blood cell maturation in animal models. Bristol Myers Squibb and Acceleron are jointly developing Reblozyl as part of a global collaboration. Reblozyl is currently approved in the U.S. for the treatment of:

anemia in adult patients with beta thalassemia who require regular red blood cell transfusions, and
anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).
Reblozyl is not indicated for use as a substitute for red blood cell transfusions in patients who require immediate correction of anemia.

U.S. Important Safety Information

WARNINGS AND PRECAUTIONS

Thrombosis/Thromboembolism

In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension

Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In patients with beta thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) ≥130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) ≥80 mm Hg. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

Embryo-Fetal Toxicity

REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post-implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose.

ADVERSE REACTIONS

Beta Thalassemia

Serious adverse reactions occurred in 3.6% of patients on REBLOZYL. Serious adverse reactions occurring in 1% of patients included cerebrovascular accident and deep vein thrombosis. A fatal adverse reaction occurred in 1 patient treated with REBLOZYL who died due to an unconfirmed case of acute myeloid leukemia (AML). Most common adverse reactions (at least 10% for REBLOZYL and 1% more than placebo) were headache (26% vs 24%), bone pain (20% vs 8%), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%) and dizziness (11% vs 5%).
Myelodysplastic Syndromes

Grade >3 (≥2%) adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%) patients.
The most common (≥10%) adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection.
LACTATION

It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose.

Please see full Prescribing Information and Summary of Product Characteristics for REBLOZYL

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision—transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

Four-year follow-up analysis from the Phase III CLL14 study showed progression-free survival rate of 74.0% in previously untreated patients with chronic lymphocytic leukemia (CLL) three years after completion of a one-year fixed-duration treatment with Venclexta plus Gazyva New Phase III MURANO study data suggested certain genetic risk factors may help tailor treatments for patients with previously treated CLL A post-hoc analysis from the Phase III VIALE-A study in newly diagnosed acute myeloid leukemia indicated increased duration of response, event-free survival and overall survival in patients who achieved undetectable minimal residual disease.

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced the latest data from three pivotal Phase III studies of Venclexta^® (venetoclax) – CLL14, MURANO and VIALE-A – to be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Virtual Congress, June 9-17 (EHA2021). Long-term follow-up data from the CLL14 and MURANO studies support the primary analysis of Venclexta in chronic lymphocytic leukemia (CLL) and the possibility of tailoring treatment approaches based on genetic risk factors. Furthermore, the latest research shows the potential of minimal residual disease (MRD) as a key measure of disease response in CLL and acute myeloid leukemia (AML).
“The data from these Venclexta combinations support our continued commitment to provide valuable therapeutic options for patients with hard-to-treat blood cancers,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “These data also advance our understanding of minimal residual disease, which we believe is a useful endpoint that may help identify patients more quickly who are in need of additional treatment.”

Four-Year Follow-Up Analysis of the Phase III CLL14 Study

This four-year post-hoc analysis of investigator-assessed progression-free survival (PFS) had a median follow-up of 52.4 months (interquartile range: 49.5-56.2 months). The fixed treatment duration (12 months) study indicated that the chemotherapy-free Venclexta plus Gazyva^® (obinutuzumab) regimen had an estimated PFS rate of 74.0% vs 35.4% for Gazyva plus chlorambucil. Importantly, the time to next treatment (TTNT) was significantly longer among patients treated with the Venclexta plus Gazyva regimen versus the comparator (four-year TTNT 81.1% vs 59.9%; HR 0.46, 95% CI [0.32-0.65], p<0.0001). Abstract #S146, oral presentation.
Furthermore, 30 months after the end of treatment, 26.9% of the Venclexta-treated patients still had undetectable MRD (uMRD) compared with 3.2% of those treated with the comparator. Undetectable MRD, sometimes referred to as MRD-negativity, means that no cancer cells could be detected using a specific and highly sensitive test, and is defined as less than one cancer cell in 10,000 leukocytes. Undetectable MRD is emerging as a measure of disease response that may be useful to consider in treatment decision-making.
Common grade 3-4 adverse events with Venclexta and Gazyva at 28 months follow-up were low white blood cell count and infections.

Substudy from the Phase III MURANO Study

Results from this substudy suggested that increased prevalence of certain unfavorable genetic risk factors negatively impacted the MRD response of patients who were retreated with Venclexta plus Rituxan^® (rituximab) after progression on treatment with that regimen. These data indicate the potential to tailor treatment approaches for patients with previously treated CLL based on genetic risk factors. Abstract #EP599, poster presentation.

Post-Hoc Analysis of the Phase III VIALE-A Study

Additionally, a post-hoc analysis from the Phase III VIALE-A study suggested the value of continued research to understand the role of MRD monitoring in AML. In the analysis, patients who achieved a composite complete remission and uMRD following treatment with Venclexta and azacitidine, a hypomethylating agent, had improved survival outcomes compared with those who were MRD-positive following treatment. The 12-month estimates for duration of response, overall survival and event-free survival for both groups are listed below:

	Achieved composite complete remission and uMRD (MRD<10 -3)	Did not achieve composite complete remission and uMRD (MRD≥10 -3)
Duration of response	81.2% (95% CI 69.3-88.9)	46.6% (95% CI 35.6-56.8)
Overall survival	94.0% (95% CI 84.7-97.7)	67.9% (95% CI 57.6-76.2)
Event-free survival	83.2% (95% CI 71.6-90.3)	45.4% (95% CI 35.2-55.0)

Adverse events of grade ≥3 (MRD<10^-3/MRD≥10^-3) were febrile neutropenia (50%/43%), neutropenia (50%/35%) and thrombocytopenia (44%/44%), similar to the overall population. Abstract #S137, oral presentation.
Genentech is collaborating with regulatory authorities and others in the industry to advance understanding of MRD. The company continues to investigate Venclexta in a robust clinical development program, including in the Phase III CRISTALLO trial in previously untreated CLL, which uses MRD as a primary endpoint.
Venclexta is approved in the United States and European Union in combination with Rituxan for the treatment of adult patients with CLL who have received at least one prior therapy; in combination with Gazyva for the treatment of adult patients with previously untreated CLL; and as a monotherapy for the treatment of CLL in the presence of 17p deletion or TP53 mutation in people who are unsuitable for or have failed a B-cell receptor pathway inhibitor.
Venclexta is also approved in the United States in combination with azacitidine, decitabine or low dose cytarabine for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. In the European Union, Venclexta is approved in combination with a hypomethylating agent for the treatment of adult patients with newly diagnosed AML who are ineligible for intensive chemotherapy.

About the CLL14 Study

CLL14 [View Source">NCT02242942] is a randomized Phase III study evaluating the combination of fixed-duration Venclexta^® (venetoclax) plus Gazyva^® (obinutuzumab) compared to Gazyva plus chlorambucil in adult patients with previously untreated chronic lymphocytic leukemia (CLL) and co-existing medical conditions. 432 patients with previously untreated CLL were randomly assigned to receive either a 12-month duration of Venclexta alongside six-month duration of Gazyva (Arm A) or six-month duration of Gazyva alongside 12-month duration of chlorambucil (Arm B). Arm A started with an initial dosing of Gazyva followed by a five-week Venclexta dose ramp-up to help reduce the risk of tumor burden. The primary endpoint of the study is investigator-assessed progression-free survival (PFS). Secondary endpoints included PFS assessed by independent review committee, minimal residual disease (MRD) status, overall response rate, complete response rate, and safety. The CLL14 study is being conducted in cooperation with the German CLL Study Group, headed by Michael Hallek, M.D., University of Cologne.

About the MURANO Study

MURANO [View Source">NCT02005471] is a Phase III open-label, international, multicenter, randomized study evaluating the efficacy and safety of fixed-duration Venclexta (venetoclax) in combination with Rituxan^® (rituximab) compared to bendamustine in combination with Rituxan (BR). All treatments were of fixed duration. Following a five-week dose ramp-up schedule for Venclexta patients on the Venclexta plus Rituxan arm received six cycles of Venclexta plus Rituxan followed by Venclexta monotherapy for up to two years total. The study included 389 patients with chronic lymphocytic leukemia (CLL), with or without 17p deletion, who had been previously treated with at least one line of therapy. A substudy from 2018 onward enrolled 34 relapsed or refractory CLL patients who progressed after initial treatment to receive Venclexta plus Rituxan as retreatment (n=25) or who crossed-over from the BR arm (n=9). The primary endpoint of the study was progression-free survival. Secondary endpoints included overall survival, overall response rate and complete response rate (with or without complete blood count recovery).

About the VIALE-A Study

VIALE-A [View Source">
NCT02993523] is a Phase III, randomized, double-blind, placebo-controlled multicenter study evaluating the efficacy and safety of Venclexta^® (venetoclax) plus azacitidine, a hypomethylating agent, compared to placebo with azacitidine, in 431 people with previously untreated acute myeloid leukemia who are ineligible for intensive chemotherapy. Two-thirds of patients (n=286) received 400 mg Venclexta daily, in combination with azacitidine, and the remaining patients (n=145) received placebo tablets in combination with azacitidine. Patients enrolled in the study had a range of mutational subtypes, including IDH1/2 and FLT3. VIALE-A met its primary and key secondary endpoints.

About Venclexta

Venclexta is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other tumors, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta blocks the BCL-2 protein and works to restore the process of apoptosis.

Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the United States and commercialized by AbbVie outside of the United States. Together, the companies are committed to research with Venclexta, which is currently being studied in clinical trials across several types of blood cancers.

In the United States, Venclexta has been granted five Breakthrough Therapy Designations by the U.S. Food and Drug Administration (FDA): one for previously untreated CLL, two for relapsed or refractory CLL and two for previously untreated acute myeloid leukemia.

Venclexta Indications

Venclexta is a prescription medicine used:

• to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
• in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:

‒ are 75 years of age or older, or

‒ have other medical conditions that prevent the use of standard chemotherapy.

It is not known if Venclexta is safe and effective in children.

Important Safety Information


What is the most important information patients should know about Venclexta?


Venclexta can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. The patient’s doctor will do tests to check their risk of getting TLS before they start taking Venclexta. The patient will receive other medicines before starting and during treatment with Venclexta to help reduce the risk of TLS. The patient may also need to receive intravenous (IV) fluids into their vein.

The patient’s doctor will do blood tests to check for TLS when the patient first starts treatment and during treatment with Venclexta. It is important for patients to keep appointments for blood tests. Patients should tell their doctor right away if they have any symptoms of TLS during treatment with Venclexta, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Patients should drink plenty of water during treatment with Venclexta
to help reduce the risk of getting TLS.

Patients should drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before the first dose on the day of the first dose of Venclexta, and each time a dose is increased.

The patient’s doctor may delay, decrease the dose, or stop treatment with Venclexta if the patient has side effects. When restarting Venclexta after stopping for 1 week or longer, the patient’s doctor may again check for the risk of TLS and change the patient’s dose.

What patients should not take Venclexta?


Certain medicines must not be taken when the patient first starts
taking Venclexta and while the dose is being slowly increased because
of the risk of increased TLS.
 

• 
  Patients should tell their doctor about all the medicines they take
  , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Venclexta and other medicines may affect each other causing serious side effects.
• Patients must not start new medicines during treatment with Venclexta without first talking with their doctor.

Before taking Venclexta, patients must tell their doctor about all of
their medical conditions, including if they:

• Have kidney or liver problems.
• Have problems with body salts or electrolytes, such as potassium, phosphorus, or calcium.
• Have a history of high uric acid levels in the blood or gout.
• Are scheduled to receive a vaccine. Patients should not receive a “live vaccine” before, during, or after treatment with Venclexta, until the patient’s doctor tells them it is okay. If the patient is not sure about the type of immunization or vaccine, the patient should ask their doctor. These vaccines may not be safe or may not work as well during treatment with Venclexta.
• Are pregnant or plan to become pregnant. Venclexta may harm an unborn baby. If the patient is able to become pregnant, the patient’s doctor should do a pregnancy test before the patient starts treatment with Venclexta, and the patient should use effective birth control during treatment and for at least 30 days after the last dose of Venclexta. If the patient becomes pregnant or thinks they are pregnant, the patient should tell their doctor right away.
• Are breastfeeding or plan to breastfeed. It is not known if Venclexta passes into the patient’s breast milk. Patients are instructed to not breastfeed during treatment with Venclexta and for 1 week after the last dose.

What to avoid while taking Venclexta:

Patients should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while they are taking Venclexta. These products may increase the amount of Venclexta in the patient’s blood.

What are the possible side effects of Venclexta?

Venclexta can cause serious side effects, including:

• Low white blood cell counts (neutropenia). Low white blood cell counts are common with Venclexta, but can also be severe. The patient’s doctor will do blood tests to check their blood counts during treatment with Venclexta and may pause dosing.
• Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with Venclexta. The patient’s doctor will closely monitor and treat the patient right away if they have a fever or any signs of infection during treatment with Venclexta.

Patients should tell their doctor right away if they have a fever or any signs of an infection during treatment with Venclexta.

The most common side effects of Venclexta when used in combination with
obinutuzumab or rituximab or alone in people with CLL or SLL include
low white blood cell count; low platelet count; low red blood cell count; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of arms, legs, hands, and feet.

The most common side effects of Venclexta in combination with
azacitidine or decitabine or low-dose cytarabine in people with AML
include
nausea; diarrhea; low platelet count; constipation; low white blood cell count; fever with low white blood cell count; tiredness; vomiting; swelling of arms, legs, hands, or feet; fever; infection in lungs; shortness of breath; bleeding; low red blood cell count; rash; stomach (abdominal) pain; infection in your blood; muscle and joint pain; dizziness; cough; sore throat; and low blood pressure.

Venclexta may cause fertility problems in males. This may affect the ability to father a child. Patients should talk to their doctor if they have concerns about fertility.

These are not all the possible side effects of Venclexta. Patients should call their doctor for medical advice about side effects.

Report side effects to the FDA at 1-800-FDA-1088 or
View Source">View Source. Report side effects to Genentech at 1-888-835-2555.

Please see the Venclexta full
View Source">
Prescribing Information, including the
View Source">
Medication Guide, for additional Important Safety Information.

About Genentech in Hematology

For more than 20 years, Genentech has been developing medicines with the goal to redefine treatment in hematology. Today, we’re investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. For more information visit View Sourcehematology" target="_blank" title="View Sourcehematology" rel="nofollow">View Source">View Source/hematology" target="_blank" title="View Source/hematology" rel="nofollow">View Source.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit View Source">View Source.